Visible-Light Photoredox Catalysis for the Synthesis of Fluorinated Aromatic Compounds

Abstract

Fluorine-containing functional groups are important motifs influencing physical and biological properties of organic compounds. Visible-light photoredox catalysis as a powerful strategy for the activation of small molecules contributed significantly to the rapid progress of new synthetic procedures allowing introduction of fluorine atoms into organic substrates. In this review, we highlight the distinct strategies for transition metal- and organic-photocatalytic fluorination of arenes and heteroarenes by a broad range of fluorinating compounds. The presented procedures are divided into two groups. The first group involves the reactions enabling a direct attachment of CF₃-, C_nF_m-, F-, CF₃O-, CF₃S-, and SO₂F- substituents to various aromatic compounds. The second group presents the tandem reactions where the formation of the aromatic system occurs after installation of the fluorine-containing group on the non-aromatic fragment of the molecule.

1. Introduction

Fluorination reactions have gained a prominent role among late-stage synthetic strategies due to the influence of fluorine atom substitution on organic compounds. Introduction of fluoroalkyl groups into organic substrates is an important transformation on account of the changes that these groups bring to molecules, such as an increase in lipophilicity, resistance to oxidation, bioavailability, increase in bioactivity, water repellent properties, metabolic stability, etc. [1,2,3,4,5,6,7,8,9]. Utilization of perfluoroalkylated molecules in material and catalytic chemistry is unprecedented [10,11,12,13,14]. Visible-light photoredox catalysis has become a prominent sector of synthetic methodology in the last several years due to its mild nature, its high functional group compatibility, and the unique mechanistic approaches it enables [15,16,17,18,19,20,21,22]. This method has become an important approach toward the catalytic fluorination of organic molecules. Some reviews support the utility and versatility of the photocatalytic reactions in the synthesis of complex fluorinated compounds [23,24,25,26,27,28,29]. Recently, the study of the introduction of fluorine-containing groups into aromatic or heteroaromatic substrates has accelerated, as evidenced by the large volume of papers published in recent years [30,31,32,33]. Remarkably, there is no current review available dedicated solely to photoinduced fluorination of aromatic compounds. This review will encompass the reactions involving the use of various fluorine-containing reactants in photocatalytic formation of fluorinated aromatic compounds in the timeframe of 2011–2022. The emphasis will be put on both synthetic outcome and reaction mechanism. This review is divided into two parts. In the first part, the photocatalytic reactions are presented involving the installation of the fluorine-containing moiety directly onto the aromatic ring. The second section involves formation of the aromatic ring after photocatalytic installation of the fluorine-containing group onto the molecule. This review does not involve photocatalytic difluoroalkylation of aromatic compounds as it has already been included in another paper [34].

2. Trifluoromethylation of Arenes

2.1. CF₃SO₂Cl as the Fluorinating Reactant

The CF₃ group enjoys a privileged role in the realm of medicinal chemistry because it can influence chemical and metabolic stability, lipophilicity, and binding selectivity [35,36]. Although common pharmacophores often bear CF₃ motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF₃ group at the start of a multi-step synthetic sequence. Thus, there has been considerable interest in development of new methodologies for highly efficient and selective incorporation of a CF₃ group into aromatic molecules. The first efficient protocol for the photocatalytic trifluoromethylation of arenes was developed by the MacMillan group (Scheme 1) [37].

The operationally simple strategy involved the use of CF₃SO₂Cl E[A/A⁻¹] = (−0.18 V vs. SCE) as the fluorinating agent in the presence of commercial photocatalyst [Ru(phen)₃]Cl₂ E[*A/A⁻¹] = (−0.9 V vs. SCE) and a household light bulb. The authors demonstrated the broad utility of this transformation through addition of •CF₃ to a number of heteroaromatic and aromatic systems. In the proposed mechanism, the reaction starts with excitation of 1 followed by reduction of CF₃SO₂Cl by the excited *[Ru(phen)₃]Cl₂ 2. The obtained CF₃SO₂Cl radical anion collapses to generate •CF₃ in an entropically driven process by the release of SO₂ and Cl¯. The electron-deficient •CF₃ is added to the most electron-rich position of arene. The resultant cyclohexadienyl radical 4 (in the case of benzene E[A/A⁻¹] = (−0.1 V vs. SCE)) undergoes oxidation by [Ru(phen)₃]³⁺ E[A/A⁻¹] = (1.31 V vs. SCE) 3 affording the respective carbocation 5 and regenerating ground-state photocatalyst. Finally, deprotonation of the cyclohexadienyl cation 5 with a suitable base provides the desired trifluoromethylated arene. The authors stress that a major benefit of the mild, visible-light-induced trifluoromethylation procedure is its amenability to late-stage synthetic trifluoromethylation of aromatic and heteroaromatic systems without the need for aryl ring pre-activation. The authors observed that trifluoromethylation of electronically deficient halide-substituted heteroaromatics (such as 2,6-dichloropyrazine) was also operative. Unsubstituted analogues of each of these heterocycles can also be trifluoromethylated, albeit with somewhat diminished efficiency. To demonstrate the applicability of the method, biologically active molecules as e.a. DNA-base uracil analogue, vitamin P, or Alzheimer’s drug precursor were efficiently fluorinated.

CF₃SO₂Cl was also used as fluorinating reactant for the selective trifluoromethylation of four different π-conjugated arenes to afford mono(trifluoromethylated) arenes in good yield (Scheme 2) [38].

The reaction requires the use of luminescent Co(III) complexes 6 or 7 as photocatalysts which are powerful photo-oxidants E[*A/A⁻¹] = (2.26 V and 2.75 V vs. SCE). A plausible reaction mechanism involves excitation of pyrene to its triplet state 8 by means of energy transfer from the excited photocatalyst 6*. Oxidative quenching via single-electron transfer of CF₃SO₂Cl affords •CF₃ with concomitant formation of the pyrenyl radical cation 9. The electron-deficient •CF₃ is added to the most electron-rich position of pyrene. The resultant CF₃-pyrenyl radical 10 then undergoes oxidation by the excited photocatalyst 6*, to generate the CF₃-pyrenyl cation 11. The two photocatalytic cycles are closed via a single electron transfer where 9 is reduced to pyrene and the reduced photocatalyst [ML₂]²⁺ is oxidized to 6. Finally, facile deprotonation of 11 with K₂HPO₄ affords the desired CF₃-pyrene. A new photoredox system in which a photoreductive activation of CF₃SO₂Cl was achieved has been developed by Blechert and coworkers (Scheme 3) [39]. In this work, heterogeneous, mesoporous graphitic carbon nitride (mpg-CN), a metal-free solid-state organocatalyst with an oxidation potential E[A/A⁻¹] = (1.3 V and 1.4 V vs. SHE, pH 7), was able to reduce CF₃SO₂Cl, affording •CF₃. With the developed method, it was possible to trifluoromethylate benzene and a great variety of heteroaromatic compounds such as pyrroles, oxazoles, furanes, thiophenes, indoles, and pyrazines in moderate to excellent yields. A variety of functional groups were tolerated, including aldehydes, esters, halides, and amides. However, the reaction suffers from double trifluoromethylation and formation of chlorinated side products.

Diaz and coworkers revealed that trifluoromethylation reactions can be successfully carried out in gel media under aerobic conditions, affording the desired products in comparable yields to those obtained in homogeneous solution (Scheme 4) [40]. A series of electron-rich 5-membered heteroarenes and electron-deficient 6-membered heteroarenes were trifluoromethylated in the presence of Ir(Fppy)₃ or Ru(phe)₃Cl₂ as the photocatalyst, CF₃SO₂Cl as the fluorinating reactant, and gelator under aerated conditions. The yields were comparable to those obtained in solution under an inert atmosphere. The further study revealed that, when the same reaction proceeded in solution in the presence of gelator at a concentration marginally below the critical gelation concentration (CGC), the final obtained product yields were ∼10−15% lower compared to the reaction carried out in gel phase at a concentration above the CGC. This effect was explained on the basis of the oxygen-blocking efficiency achieved with the gel network. The authors stress that gel media seem to be a promising candidate to facilitate photochemical reactions under aerobic conditions, outcompeting the MacMillan procedure requiring a strict inert oxygen-free atmosphere.

2.2. CF₃I as the Fluorinating Reactant

CF₃ radicals can be generated under mild, neutral conditions from commercially available and relatively inexpensive CF₃I E_ox[A/A⁻¹] = (−1.52 V vs. SCE) [41,42,43,44,45,46,47]. However, the gaseous state of CF₃I makes it hard to handle, causing difficulties in knowing the exact concentration present in the reaction mixture. Ye and coworkers have reported the trifluoromethylation of arylboronic acids by applying their strategy of merging photoredox catalysis with transition metal catalysis (Scheme 5) [48]. The combination of the Cu/Ru dual catalytic system has enabled the trifluoromethylation of a wide variety of aromatic and heteroaromatic substrates bearing many common functional groups. According to the presented mechanism, CF₃I is reduced by the reduced photocatalyst [Ru(bpy)₃]Cl₂ 12 with formation of •CF₃ 13. Addition of •CF₃ to the copper(II) species 15 formed in the photocatalytic cycle from the Cu(I) salt 14 oxidizes the metal to give the high-valent trifluoromethyl−copper(III) species 16. Transmetalation of arylboronic acid 17 to give aryl−copper(III) intermediate 18 is followed by aryl-CF₃ bond-forming reductive elimination to give the final product and regenerate the copper(I) species 14.

The interesting extention of this work reported by the Ritter group involves a site-selective late-stage introduction of trifluoromethyl groups into arenes using Cu-CF₃ as the radical source (Scheme 6) [49]. The Cu-CF₃ reagent was obtained by mixing CuSCN, CsF, and TMSCF₃ at 23 °C in DMF prior to addition of the Ru(II) catalyst and thiantrenium salt. The two-step procedure entails exquisitely selective thianthrenation followed by chemoselective photoredox-mediated trifluoromethylation of the aryl thianthrenium salts. The reaction proceeds with broad functional group tolerance, even for complex small molecules on the gram scale. The proposed mechanism involves oxidation of Cu(I)-CF₃ 19 by the excited Ru(II) 20, affording Cu(II)-CF₃ 21, which is followed by oxidative addition of the aryl radical 22 forming the aryl−copper(III) intermediate 23. The aryl radicals 22 are formed upon C-S bond fragmentation of the reduced thianthrenium salt 25 which is obtained in the photocatalytic cycle via single-electron transfer from Ru(I) 26 to 24. The aryl-CF₃ bond-forming reductive elimination of 23 gives the final product. However, the additional experiments performed by the authors involving a Stern–Volmer analysis and trapping of radicals by TEMPO suggest that the reaction occurs not only via a CF₃ radical pathway. Recently, Cho and coworkers reported the trifluoromethylation of electron-rich heterocycles with Ru(bpy)₃Cl₂ as the photosensitizer and CF₃I as the CF₃ radical source (Scheme 7) [50].

A variety of aromatic compounds were transformed into trifluoromethylated products under mild reaction conditions. In the proposed mechanism, Ru(bpy)₃²⁺ 27 is excited by visible light, providing *Ru(bpy)₃²⁺ 28 that is then reductively quenched by an amine to produce Ru(bpy)₃⁺ 29 and the ammonium radical cation 30. The Ru(bpy)₃⁺ species 29 in turn performs a single-electron reduction of the F₃C-I bond, regenerating 27 and forming a carbon-centered •CF₃. Finally, coupling of this electron-deficient radical with an electron-rich heterocycle 31 and the oxidation of the resulting radical 32 to 33 followed by rearomatization gives the trifluoromethylated product. The Fukuzumi group reported the use of cyclometalated platinum(II) complexes as photocatalyst for trifluoromethylation reactions (Scheme 8) [51].

A series of indoles and pyrroles were trifluoromethylated in good to excellent yields upon reaction with N,N,N’,N’-tetramethylethylenediamine as an electron donor and CF₃I. According to the proposed mechanism, photoexcitation of the platinum(II) catalyst 34 would promote an electronic transition to a singlet MLCT state which would undergo fast intersystem crossing to a triplet MLCT state 35. Reaction between this triplet state and trifluoromethyl iodide affords the CF₃ radical that can be added to heteroaromatic substrates to give the desired aryl radical 36. The final product can be formed by oxidation of 36 to 37 followed by addition of I^¯ and dehydrohalogenation with amine. The alternative pathway involves iodination of 36 with CF₃I via a chain propagation mechanism followed by dehydrohalogenation with amine. Reductive regeneration of the platinum(II) in the presence of a sacrificial electron donor 36 or amine would then close the catalytic cycle.

2.3. Hypervalent Iodine and Sulfur Compounds as the Fluorinating Reactants

Hypervalent iodine(III) reagents are widely used in organic synthesis, because of their low toxicity, strong electrophilicity, and valuable oxidizing properties [52,53,54,55,56]. The Scaiano group decided to employ electrophilic CF₃ reagents, such as Togni hypervalent-iodine compounds, for the trifluoromethylation of electron-rich heterocycles. Using methyl blue (MB) as a photocatalyst and TMEDA as the sacrificial reductant, trifluoromethylation of electron-rich heterocycles was demonstrated, which proceeded in moderate to good yield (Scheme 9) [57].

A possible mechanism for the catalytic formation of •CF₃ involves formation of the triplet state of MB 38 upon visible light irradiation. The excited photocatalyst can be quenched by amine (TMEDA) to form the semireduced MB radical 39 and an α-amino radical 40. Both of these species can in turn reduce Togni reagent 41, resulting in the release of a •CF₃ which is added next to the aromatic molecule, affording the final product. At the same time, Ma and coworkers developed the first visible-light-induced Ir-catalyzed radical trifluoromethylation of free anilines with Togni reagent at room temperature (Scheme 10) [58]. A variety of aniline derivatives have been tested and high functional group tolerance was observed, indicating that the method can be used for the late incorporation of a CF₃ group into an aniline moiety. According to the mechanism, single-electron transfer from the excited photocatalyst 42 to Togni reagent 43 generates a strong oxidant 44 and 45 which would then collapse to •CF₃ 46. The obtained 46 is added to the most electron-rich position of aniline derivative to form the radical 47. Subsequently, the cation species 48 is formed upon oxidation with strong oxidant 44. Finally, deprotonation of 48 could afford the final product.

In the search for new trifluoromethylation reactions with inexpensive and easily handled •CF₃ sources, the Quing group developed a practical visible-light-induced decarboxylative trifluoromethylation of (hetero)arenes using the easily accessible [bis(trifluoroacetoxy)iodo]perfluorobenzene as the trifluoromethylating reagent (Scheme 11) [59]. This method proved to be tolerant of various (hetero)arenes and functional groups, however, in some cases, the trifluoromethylated products were obtained as a mixture of isomers. Meanwhile, electron-deficient heteroarenes (pyridines, pyrimidines, pyrazines, and thiazoles) were also amenable to the reaction. The plausible reaction mechanism involves oxidation of *Ru(bpy)₃²⁺ E[*A/A⁻¹] = (−0.81 V vs. SCE) by 49 E[A/A⁻¹] = (−0.08 V vs. SCE), affording the iodanyl radical 50. The Stern−Volmer fluorescence quenching studies confirmed that 49 could quench *Ru(bpy)₃²⁺ effectively. Subsequently, intermediate 50 undergoes a homolytic scission of the I−O bond to generate pentafluoroiodobenzene and a trifluoroacetoxy radical 51. The resulting radical 51 extrudes CO₂ to generate the •CF₃, which is then added to the arene 52 for the formation of intermediate 53. Radical 53 might be oxidized by Ru(bpy)₃³⁺ (path A) and/or 49 (path B) to afford the corresponding cation 54. Finally, intermediate 54 undergoes deprotonation to give the desired product. It is noteworthy that pentafluoroiodobenzene can be recycled and could be used for the preparation of 49.

The commercially available dimesithylsulfoniumtrimethyl trifluoromethanesulfonate (dMesCF₃) was applied as the •CF₃ source to a trifluoromethylation of aryl bromides through dual copper-photoredox catalysis (Scheme 12) [60]. The mechanism is similar to that presented in Scheme 4, however, Ir(dFFppy)₂(4,4′-dCF₃bpy)PF₆ E[*A/A⁻¹] = (+1.55 V vs. SCE) was used as photocatalyst. During the reaction, •CF₃ is generated by reduction of dMesCF₃ 55 in the photocatalytic cycle. Noteworthily, tris-(trimethylsilyl) silanol 56 E[A/A⁻¹] = 1.54 V is oxidized in the photocatalytic cycle to afford after the rearrangement the silyl radical 57 which is then engaged in the bromine atom abstraction, affording the respective aryl radical 58. The oxidative addition of •CF₃ to the Cu(I) species 59 gives the Cu(II) intermediate 60 and, followed by the oxidative addition of the aryl radical 58, affords the respective Cu(III) adduct 61. Reductive elimination from this high-valent Cu(III) intermediate yields the desired product and simultaneously regenerates Cu(I) catalyst 59. A broad range of electronically differentiated parasubstituted bromoarenes including fused cyclic motifs were found to give good to excellent yields of the desired products. Regarding the scope of heteroarylbromides, pyridine derivatives as well as bromopyrazines, pyrimidines, and pyridazines or five-membered heteroarylbromides, such as imidazoles, pyrazoles, and thiazoles, were competent substrates, providing the desired products in good yields.

2.4. Trifluoromethyl Acid and Anhydride as the Fluorinating Reactants

Trifluoroacetic acid and its anhydride (TFAA) are desirable •CF₃ sources from the perspective of availability and cost, but have traditionally proven challenging to utilize because of the high oxidation potential E[A/A⁻¹] > 2.4 V of the CF₃COO⁻ anion formed during reaction. Stephenson reported a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to affect a facile decarboxylation to •CF₃ (Scheme 13) [61]. Pyridine N-oxide was identified as the reagent of choice for the formation of a reducible TFAA adduct E[A/A⁻¹] = (−1.10 V vs. SCE). The reagent combination is effective in equal stoichiometry with respect to the substrate, and is sufficiently inexpensive for large-scale implementation. Furthermore, following cleavage of the weak N–O bond and CO₂ extrusion, the generation of pyridine as a byproduct is a highly beneficial design feature, preventing the need for exogenous base. Using this methodology, trifluoromethylation of vinyl, aryl, and heteroaryl substrates was performed in acetonitrile, with 1–2 equivalents of pyridine N-oxide providing generally optimal results. In some cases, however, Friedel–Crafts, N-, and O-acylation with trifluoroacetic anhydride was also observed. Importantly, the reaction was found to be tolerant of air and moisture. The same group later reported the use of 4-phenylpyridine N-oxide as a redox trigger which improved the trifluoromethylation yields and allowed a kilogram scale-up in a flow reactor [62]. The trifluoromethylation protocol developed by the Jin group is worth noting (Scheme 14). The reaction requires the use of trifluoroacetic acid in the presence of ruthenium catalyst and diaryl sulfoxides. Various heteroarenes were successfully trifluoromethylated, however, the exact role of diarylsulfoxides in the reaction mechanism is unclear [63].

2.5. Sodium Triflinate as the Fluorinating Reactant

Sodium triflinate CF₃SO₂Na (Langlois reagent) can be regarded as an easy-to-handle, inexpensive, and solid trifluoromethylating agent, capable of generating CF₃ radicals in the presence of a strong oxidant (e.g., t-BuOOH) [64,65]. The Itoh group reported the visible-light-induced trifluoromethylation of arenes and heteroarenes using CF₃SO₂Na catalyzed by anthraquinone-2-carboxylic acid AQN (Scheme 15) [66].

According to the proposed mechanism, the triflinate anion 62 E[A/A⁻¹] = (+0.6 V vs. SCE) is oxidized to 63 by the excited photocatalyst 64 E[A/A⁻¹] > (+1.5 V vs. SCE). The obtained 63 decomposes, affording •CF₃ and SO₂. The radical addition of •CF₃ to an electron-rich position of the aromatic ring, followed by oxidation of the generated radical 65 to cation 66 by •CF₃ and the concomitant deprotonation, afforded the final product. The easy oxidation of the reduced photocatalyst 67 E[A/A⁻¹] = (−1.3 V vs. SCE) by SO₂ E[A/A⁻¹] = (−1.1 V vs. SCE) produced by cleavage of 63 regenerates the ground state of the photocatalyst. Alcazar and coworkers reported a continuous-flow protocol for the trifluoromethylation of arenes, heteroarenes, and benzofused heterocycles relying on the use of solid CF₃SO₂Na as the trifluoromethylating agent, the iridium complex [Ir{dF(CF₃)ppy}₂](dtbpy)]PF₆ as the photoredox catalyst, and (NH₄)₂S₂O₈ as the external oxidant (Scheme 16) [67].

This methodology enabled trifluoromethylation of caffeine, indoles, benzimidazoles, pyridines, pyridones, pyrazoles, and unactivated arene substrates in moderate to excellent yields within only 30 min of reaction time. The main reason for the remarkable acceleration of the reaction rate lies in the improved irradiation of the reaction mixture obtained in the microflow reactor (Vapourtec). The luminescence quenching studies performed by the authors suggest that the excited state of the photocatalysts E[*A/A⁻¹] = (1.21 V vs. SCE) can be reductively quenched by the Langlois reagent E[A/A⁻¹] = (+1.02 V vs. SCE), thus generating •CF₃.

The Ackermann group developed the first electrophotochemical trifluoromethylation enabled by the cooperative action of electrochemistry and photochemistry in the presence of [Mes-Acr⁺]ClO₄⁻ as a photocatalyst and CF₃SO₂Na as the fluorinating agent (Scheme 17) [68]. This strategy avoids the use of expensive and toxic chemical oxidants. The mechanistic considerations suggest the initial irradiation of the organic dye Mes-Acr⁺ 68 to generate its oxidized excited state Mes-Acr⁺* 69. A single-electron transfer process between 69 E[*A/A⁻¹] = (+2.06 V vs. SCE) and the sulfinate anion results in the generation of the acridinyl radical 70 and formation of •CF₃. Anodic electrooxidation of the acridinyl radical 70 subsequently regenerates the ground state catalyst Mes-Acr⁺. The addition of •CF₃ to arene affords the radical adduct 71 which can be oxidized to the cationic Wheland complex 72 by Mes-Acr⁺ or directly at the anode. Finally, proton abstraction delivers the desired product, whereas protons are reduced to generate H₂ at the cathode. The reaction features a broad substrate scope and a high tolerance of synthetically useful functional groups including furan, thiophene, benzofuran, benzo[b]thiophene, indole, quinoline, and pyrimidine derivatives. Remarkably, the reaction allowed for the efficient conversion of naturally occurring motifs, such as caffeine, pentoxifylline, doxofylline, theobromine, methyl estrone, and tryptophan derivatives, thereby highlighting the utility of the electrophotochemical transformation strategy for late-stage trifluoromethylations. The electrophotochemical trifluoromethylations were further achieved in a flow setup affording trifluoromethylated mesitylene in high yield.

In recent years, many other methods for photoredox catalytic oxidation of CF₃SO₂Na have been established. Sharada and coworkers reported a methylene blue-promoted regioselective C3-trifluoromethylation of 2H-indazoles (Scheme 18) [69].

The combination of photocatalysis and hypervalent iodine reagent provides a practical approach to a variety of trifluoromethylated indazoles in 35−83% yields. In the proposed mechanism, the indazole 73 undergoes oxidation by the excited photocatalyst MB and then the photocatalytic cycle is closed via reduction of the photocatalyst by the acetate radical. On the other hand, the fluorinating agent is formed in the reaction of CF₃SO₂Na with phenyliodine(III) diacetate and the obtained adduct decomposes spontaneously, affording the •CF₃. The addition of •CF₃ to the oxidized indazole 74 followed by proton abstraction affords the final product. The presented mechanism is in contrast to that previously reported (Scheme 11) where the •CF₃ is formed after reduction of hypervalent compound in the photocatalytic cycle. In the visible-light-mediated ortho-C−H trifluoromethylation of aniline derivatives using an Eosin Y/Cu dual catalytic system, CF₃SO₂Na is oxidized by SO₄^˙¯ formed by reduction of (NH₄)₂S₂O₈ (Scheme 19) [70].

The trifluoromethyl radical would be rapidly captured by Cu(II) species 75, affording a Cu(III)-CF3 intermediate 76. The radical 77 generated by the oxidized photocatalyst would be oxidized by Cu(III) species 76 and coordinate with Cu-CF3 to form 78. Complex 78 undergoes intramolecular trifluoromethylation, affording intermediate 79 and regenerating the Cu catalyst 75. Finally, intermediate 79 tautomerizes to afford the final product. It should be stressed that the reaction is regiospecific, affording exclusively ortho-substituted aniline derivatives. The oxidation of CF₃SO₂Na by SO₄^¯ to form the •CF₃ is also a key step in the trifluoromethylation of arylcarbamates using 4,5-dichlorofluorescein (DCFS) as a photocatalyst [71]. In this case, however, the steric effect of DCFS would increase the steric hindrance of the ortho- and meta-positions on the phenyl ring, leading to the highly para-selective trifluoromethylation. Wang and coworkers developed a visible-light-induced Pd-catalyzed ortho-trifluoromethylation of acetanilides with CF₃SO₂Na (Scheme 20) [72]. Interestingly, both the substrate and products undergo excitation by a blue LED (410–415 nm) to generate the excited species, which acts as a photocatalyst. It was revealed that the ¹O₂ generated via energy transfer between excited photocatalyst and ³O₂ can react with CF₃SO₂Na via single electron transfer to afford the superoxide radical anion O₂^˙¯ 80 and a CF₃SO₂ radical 81, which decomposes, generating a CF₃ radical. On the other hand, the Pd catalytic cycle is initiated by C–H activation to afford palladacycle intermediate 82, which undergoes a reaction with the formed •CF₃ to afford 83. The oxidation of 83 to 84 is followed by reductive elimination affording the final product and regenerating the Pd catalyst.

3. Trifluoromethylthiolation and Trifluoromethoxylation of Arenes

The Wangelin group reported a protocol of radical aromatic trifluoromethylthiolation of arenediazonium salts that is based on the facile generation of intermediate aryl radicals (Scheme 21) [73].

Bis(trifluoromethyl) disulfide (F₃CS-SCF₃), which was used as the fluorinating species, is a commercial reagent that can also be freshly prepared by a literature procedure [74]. A series of arenediazonium salts were transformed into the desired aryl trifluoromethylsulfides in the presence of [Ru(bpy)₃]Cl₂ under irradiation with blue light (450 nm, 3.8 W LED) in moderate to good yields. The authors postulate a radical mechanism that is initiated by the photocatalytic reduction of the diazoacetate adduct formed in the reaction of arenediazonium salt with sodium acetate affording the aryl radical Ar•. The obtained Ar• undergoes rapid reaction with (SCF₃)₂ affording Ar-SCF₃ and generating the trifluoromethylthiyl radical F₃CS•. The formation of Ar• and F₃CS• was confirmed by trapping with TEMPO. The authors hypothesize recombination of F₃CS• with suitable nucleophiles (Nu = DMSO or acetate anion) during the reaction. Back-electron transfer (formally from the elusive [NuSCF₃]^•−) could be a potential pathway of photocatalyst regeneration.

Trifluoromethoxylation of arenes can be performed employing either radical fluoroalkoxylating reagents or some nucleophilic trifluoromethoxylating sources [75]. However, the photocatalytic approach of the synthesis of trifluoromethoxyarenes is worth mentioning. Ngai and coworkers reported the catalytic intermolecular trifluoromethoxylation of (hetero)arenes under photocatalytic conditions (Scheme 22) [76]. The key to success of this procedure was development of an easy-to-handle, photoactive trifluoromethoxylating reagent 85. This protocol was applicable to simple arenes containing common function groups including halides, carboxylic acids, ketones, esters, ethers, nitriles, carbonates, and phosphine oxides. Later, the same group reported a redox-active cationic reagent 86 capable of forming the OCF₃ radical exclusively upon photocatalytic reduction [77]. This reagent is also applicable to the catalytic (hetero)aryl trifluoromethoxylation including a number of biorelevant compounds.

At the same time, Togni and coworkers disclosed the work on radical trifluoromethoxylation using a pyridinium-based reagent 87 [78]. A variety of simple aryl trifluoromethyl ethers bearing common functional groups were prepared and the reaction was also applicable to more complex structures including e.a. Femara^® (anticancer treatment) or procymidone (a fruit fungicide). In the case of 85 and 87, the reaction occurs via photoreduction of these compounds with the formation of the •OCH₃ followed by the addition of •OCH₃ to the arene and the concomitant oxidation–deprotonation affording the final product. However, for 86 an alternative mechanism is proposed as it was found by the authors that the formation of the •OCF₃ via the reduction of 86 by excited Ru(bpy)₃(PF₆)₂ is unlikely. The reaction starts with the photoexcitation of the OCF₃ reagent 86. This direct excitation is followed by a homolytic cleavage of the N-OCF₃ bond to afford •OCF₃ and an N-centered benzimidazole radical 88. The •OCF₃ adds to an arene to afford the radical 89, while 88 is reduced by *Ru(bpy)₃ to benzimidazole anion 90 (path A). The subsequent single-electron transfer from 89 to Ru(III) affords cyclohexadienyl cation 91 (path B), deprotonation of which restores the aromaticity and yields the desired aryl trifluoromethyl ether.

4. Perfluoroalkylation of Arenes

Even though several perfluorinated compounds are commercially available, the development of novel methods for efficient and selective introduction of fluorinated motifs is a growing area of interest because of the expansion of applications in medicinal, synthetic, industrial, and agricultural chemistry [79,80,81,82]. Synthetic procedures for direct couplings with perfluoroalkyl groups are relatively limited compared to trifluoromethylations. Perfluoroalkylated arenes were usually obtained utilizing the procedures developed for trifluoromethylation of aromatic compounds. For example, the conditions applied by Ye and coworkers [48] for trifluoromethylation of arylboronic acids using CF₃I in a Cu/Ru dual catalytic system can also be utilized for perfluoroalkylation reactions. Using commercially available perfluorobutyl and perfluorodecyl iodides, the respective perfluoroalkylated biphenyls were obtained in good yields (Scheme 23). Similarly, the procedures of trifluoromethylation of arenes can also be extended for installation of -C₂F₅, -C₃F₇, -C₆F₁₃, and -C₈F₁₆ motifs into the aromatic system of alkoxybenzenes and nitrogen-based heterocycles [62,63,66,67].

A simple and straightforward photocatalytic perfluoroalkylation method has been developed in continuous microflow, using commercially available [Ru(bpy)₃]Cl₂ as a photocatalyst and selected perfluoroalkyl iodides [83]. A selection of five-membered heteroaromatics were successfully perfluoroalkylated within several minutes. This flow synthesis technology exhibits merits such as high reaction yield (55–88%), mild reaction conditions (room temperature), atmospheric pressure, and excellent scale-up potential, which should allow easy implementation of this methodology in both academia and industry (Scheme 24). In the same year, the Noël group developed a remarkably efficient visible-light-photoinduced catalytic perfluoroalkylation of pyrroles and indoles in continuous flow using Eosin Y as the photoredox catalyst [84]. The Postigo group extended these studies, presenting a visible-light-driven transition-metal-free radical aromatic substitution reaction of aniline derivatives with perfluoroalkyl iodides in the presence of cesium carbonate as base and inexpensive Rose Bengal (RB) as organophotocatalyst in MeCN as solvent (Scheme 25) [85]. A series of perfluoroalkyl-substituted aniline derivatives were obtained in good to excellent yields, however, in the case of unsubstituted aniline the formation of the mixture of para- and ortho-isomers was observed. The proposed mechanism involves the excitation of RB 92 to RB* 93, which transfers an electron to n-C₄F₉I, generating •C₄F₉ radical 94 and the radical cation RB^·+. The addition of 94 to aniline affords the radical 95 which is next oxidized by n-C₄F₉I to 96. This step can propagate the chain process of the formation of •C₄F₉. The hydrogen abstraction from 96 by Cs₂CO₃ affords the final product. The authors hypothesize that the RB^·+ radical cation also accepts an electron from Cs₂CO₃ to regenerate RB. The fact that addition of Cs₂CO₃ to the photocatalytic reactions significantly improved the perfluorobutylation yields could support the role of the base as an electron-donor adjuvant to regenerate the catalyst.

A series of aniline derivatives were efficiently perfluoroalkylated using fac-Ir(ppy)₃ (0.1%) in the presence of K₂CO₃ in DCM at room temperature under blue light irradiation (Scheme 26) [86].

The substrates bearing electro-neutral and electro-donating groups underwent the perfluoroalkylation smoothly and furnished products in good to excellent yields. For para-substituted derivatives, only ortho-substituted aniline was formed, however, a mixture of regio-isomers with an almost 1/1 ratio (ortho/para) was obtained when methyl 3-amino-4-iodobenzoate was examined. Meanwhile, only para-substituted perfluoroalkylated aniline was formed when di-ortho-substituted aniline was employed as a substrate. According to the proposed mechanism, the reaction starts with the excitation of the photocatalyst [Ir(ppy)₃] 97 with blue LEDs. Subsequent single-electron transfer from 98 to R_fI generates perfluoroalkyl radical 99 and Ir(IV)(ppy)₃ 100. The newly formed radical intermediate reacts with free aniline to produce intermediate 101, which is oxidized by 100, followed by the abstraction of a proton with the base to provide the perfluoroalkylated product. The Ritter group has revealed that photoredox-catalyzed cross-coupling of aryl thianthrenium salts with a copper-based trifluoromethyl reagent for a site-selective trifluoromethylation can also be utilized for the introduction of a pentafluoroethyl group (Scheme 27) [49]. The mesoporous graphitic carbon nitride (mpg-CN) photocatalyst utilized by the Blechert group to trifluoromethylate various arenes was further applied to obtain 2-perfluorobutyl pyrrole (Scheme 28) [39]. High reactivity (85%) was observed in the case of perfluorobutyl sulfonyl chloride as the fluorinating agent, however, double fluoroalkylation product at positions 2 and 5 of pyrrole was also obtained (8%). The use of perfluorobutyl sulfonyl fluoride showed only a slow reaction with a low conversion to the desired product (17%). This can be explained by the stronger S-F bond compared to the S-Cl bond that inhibits a fast degradation after reduction to generate the perfluoroalkyl radical. On the other site, using perfluorobutyl iodide, the reaction was slower than with perfluorobutyl sulfonyl chloride, but a good yield of 68% of the desired product was achieved.

Wang and coworkers reported a photocatalyzed, copper-mediated system for ortho-perfluoroalkylation of 8-aminoquinoline-derived benzamides using Eosin Y as the photocatalyst (Scheme 29) [87].

A series of benzamides were selectively perfluoroalkylated at the ortho-position. A plausible mechanism involves formation of cyclometalated complex 103 from C-H activation of 102 with copper salt. Perfluoroalkyl radicals formed by the reaction of perfluoroalkyl iodides with excited photocatalyst react with 103 to form a Cu III complex 104. Finally, reductive elimination of 104 affords the desired product. Arenes could also be perfluoroalkylated using perfluoroalkyl iodides in the presence of heterogenic photocatalysts such as TiO₂, carbon nitride or via formation of EDA complexes [88,89,90].

To extend the application of hypervalent iodine(III) acetates utilized by the Qing group, the analogous fluoroalkylation reactions were examined using perfluoroethyl and perfluoropropyl derivatives C₆F₅I(OCOR_f)₂ (Scheme 30) [59].

These reactions proceeded smoothly under the standard conditions, resulting in the pentafluoroethylated and heptafluoropropylated products in moderate yields.

5. Monofluorination of Arenes

Although various fluorination procedures have been developed, the known synthetic methods usually involve the use of toxic and dangerous atomic fluorine sources, often affording a mixture of mono- and difluorinated compounds [91,92,93,94]. Radical fluorination reactions have been developed as an efficient methodology for the fluorination of complex molecules [95,96,97]. However, these reactions require further study mainly involving the improvement of regiospecificity and the ability to use cheap and readily available starting materials. The concept of visible-light-driven photocatalysis has been proved attractive for the direct C-F bond formation. Fukuzumi and coworkers reported the photocatalytic system using tetraethylammonium fluoride tetrahydrogen fluoride salt (TEAF•4HF) as fluorinating reagent in the presence of 3-cyano-1-methylquinolinium perchlorate (QuCN⁺ClO₄⁻) as photocatalyst (Scheme 31) [98]. Using acetonitrile as a solvent under irradiation of a 500 W xenon lamp, fluorobenzene was obtained in 20% yield after 50 min of irradiation. Chloro- and bromobenzene were also fluorinated, however, the corresponding para-substituted products were formed in low yield (7 and 6%). The proposed mechanism involves reaction of the excited photocatalyst 105 with arene 106 to generate arene radical cation 107 existing in equilibrium with its dimer radical cation 108. TEAF•4HF reacts with 107, affording the aryl radical 109. The O₂^•− radical formed upon reduction of oxygen in the photocatalytic cycle abstracts hydrogen from radical 109 to afford the desired fluorinated product.

The Nicewicz group developed an organic photoredox system for direct arene C−H radiofluorination, using ¹⁸F⁻NBu₄⁺ as a fluorinating agent and molecular oxygen as an oxidant [99]. This procedure is especially valuable because fluorine-18 is the most widely used positron emission tomography (PET) isotope. Using laser irradiation to excite an acridinium photocatalyst, unactivated arenes were effectively fluorinated, affording a wide range of ¹⁸F-labeled arenes and heteroaromatics, including pharmaceutical compounds and PET tracers. In order to replace the expensive laser light source and to exclude the necessity of bubbling the oxygen through the reaction vessel, the same group developed a photoredox system and apparatus that allow for direct C−H radiofluorination, using a readily available 425 nm LED light source (Scheme 32) [100]. In order to increase the overall light influx needed, the reactions were performed using a microtubing reactor that greatly increased the surface area being exposed to the light source. After optimization studies, tert-butylperoxy acetate (TBPA) was selected as the optimal oxidant in tert-butanol as the optimal solvent. The availability of the wide range of organic photocatalysts prompted the authors to perform a catalyst screening. Generally, acridinium salts were the most suitable catalysts for radiofluorination and the compound 110 was selected as the most efficient photocatalyst. Amongst twenty-two examples of examined arenes, eleven of the substrates demonstrated improved yields, and ten of them showed comparable or decreased yields. A significant improvement (23% yield) was observed for 4-chromanone for which the previous method proved to be ineffective. The regioselectivity observed in this study generally follows the same trends observed in previous photoredox arene C−H fluorination studies affording functionalization occurring ortho or para to an electron-donating group. The mechanistic proposal for this reaction involves oxidation of an arene 111 by the excited photocatalyst 110* affording the carbocation 112 which undergoes nucleophilic attack by F⁻. The oxidant is presumed to react with the radical 113 to lead to alkylperoxyl radical 114. Intramolecular hydrogen atom transfer and extrusion of an alcohol unit (R’OH) would then furnish the fluorinated arene. The radical scavenger (TEMPO) reacts rapidly with the cyclohexadienyl radical via hydrogen atom abstraction to yield the corresponding aromatic compound.

Ritter and coworkers revealed that metallophotoredox catalysis combined with exquisitely selective aromatic C–H functionalization by thianthrenation can now be employed to produce synthetically valuable fluorinated analogues of complex small molecules (Scheme 33) [101]. Fluorination is successful on electron-deficient, -neutral, and -rich arenes, as well as on substrates that bear ortho-substituents. The reaction is tolerant towards aldehydes, esters, heterocycles, benzyl ethers, carbamates, amides, acid-sensitive glycosidic linkages, and ketones. Protic groups, which are not compatible with other nucleophilic and electrophilic transition metal-catalyzed fluorination reactions, are tolerated in copper-mediated photoredox fluorination. In the proposed mechanism, arylthianthrenium salt 115 is reduced by the photocatalyst 116, repelling thianthrenium 117 and affording the aryl radical 118. The obtained radical 118 undergoes addition to the Cu(II) compound 119 followed by complexation with F⁻, affording the intermediate 120. The reductive elimination of 120 gives the final product and the Cu(I) 121 compound which is next oxidized to Cu(II) 119 by the thianthrenium radical 122 obtained after oxidation of thianthrene in the photocatalytic cycle. The mechanism of the reaction is accurately supported by kinetical experiments (fragmentation rates of arylthianthrenium salts), Stern–Volmer measurements (effective reductive quenching of the excited iridium photocatalyst by thianthrene), and TEMPO trapping studies (formation of adducts with aryl radicals).

6. Fluorosulfonation of Arenes

Tlili and coworkers reported the first photocatalytic metal-free procedure for the synthesis of arylsulfonyl fluorides (Scheme 34) [102]. The reaction involves the use of aryl diazonium salts, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as the fluorine source, and the cyanoarene photocatalyst 123 under blue LED irradiation. The mild conditions afforded a broad scope and high functional group tolerance including electron-donating and -accepting substituents in benzene derivatives. Steric hindrance was not deleterious to the reaction outcome, since up to 80% yields were reached for ortho-substituted methoxyphenyl derivative. Interestingly, heterocyclic compounds could also be converted to their corresponding sulfonyl fluorides in moderate yields. According to the proposed mechanism, photoinduced reduction of the diazonium salt by the excited 123* yields arene radical 124 and radical cation photocatalyst 125. Subsequently, the aryl radical collapses with SO₂ to form a new radical tosyl species 126. The released DABCO 127 regenerates the photocatalyst 123 in its ground state and 128. The latter may combine with 126 to generate the sulfonium salt intermediate 129. The nucleophilic fluorine attack on 129 affords the final product and regenerates DABCO. It should be stressed that the presented mechanism is supported by quantum-mechanical calculations.

7. Tandem Photocatalytic Fluorination–Aromatization Processes

The previously reported general methods for the synthesis of aromatic derivatives bearing a fluorine or perfluoroalkyl group in a specific position display in some cases poor regioselectivity and require the direct use of preformed or commercially available aromatic counterparts. The alternative strategy exploits tandem reactions by combining organo-photoredox-catalyzed radical fluoroalkylation of the non-aromatic part of the molecule followed by a reaction sequence leading to aromatization [103,104]. However, in this review article, the emphasis will be put exclusively on reactions leading to the installation of the fluorinated group directly into the aromatic core. Yu and coworkers developed a convenient approach to obtain 6-alkylated phenanthridines using various biphenyl-based isocyanides and alkyl bromides in the presence of fac-Ir(ppy)₃ as the photocatalyst (Scheme 35) [105]. The reaction proceeded at room temperature in good to excellent yields in the absence of external stoichiometric oxidants. Within a broad substrate scope, two fluorinated bromides were used, affording the respective perfluoroalkylated products. Based on the authors’ observations, photocatalyst fac-Ir(ppy)₃ is irradiated to the excited state 130 which is oxidatively quenched by 131 with the formation of 132 and a radical species 133. The radical 133 is added to 134 to produce the imidoyl radical intermediate 135, which undergoes intramolecular cyclization to give the radical intermediate 136. The intermediate 136 is then oxidized by 132 to form 137 and regenerating fac-Ir(ppy)₃. Ultimately, deprotonation assisted by the base yields the final product.

The extention of this reaction type involved the use of Umemoto reagent 138 E[A/A⁻¹] = (−0.61 V vs. SCE) in the presence of Ir(ppy)₂(dtbbpy)PF₆ as the photocatalyst (Scheme 36) [106]. The methodology presented by the authors provides access to highly fuctionalized 1-trifluoromethylisoquinolines under mild conditions in good to excellent yields. The proposed mechanism involves generation of •CF₃ and radical cation 139 via homolytic cleavage of 138 (path A) assisted by visible light which is supported by theoretical calculations. The radical cation 139 E[A/A⁻¹] = (0.06 V vs. SCE) is reduced to sulfide 140 by the excited photocatalyst 141 E[A/A⁻¹] = (−0.75 V vs. SCE). The •CF₃ species is trapped by isocyanide 142 to give radical 143, which undergoes intramolecular cyclization affording radical 144. The aryl radical 144 E[A/A⁻¹] = (−0.65 V vs. SCE) is then oxidized by Ir(IV) E[A/A⁻¹] = (1.14 V vs. SCE) to aryl cation 145 and regenerates Ir(III). Finally, deprotonation assisted by a base yields the final product. The authors suggest that •CF₃ can also be generated upon direct reduction of 138 by the excited photocatalyst 141 (path B).

Li and coworkers developed a radical-triggered cyclization of o-alkenyl aromatic isocyanides prepared from accessible starting materials (Scheme 37) [107]. The reaction provides a general and efficient method for the synthesis of 4-CN-2-CF₂H-containing quinolines under visible-light photoredox catalysis in a one-pot synthetic procedure. A wide scope of o-alkenyl aromatic isocyanides bearing different electron-withdrawing and electron-donating groups at the ortho-, meta-, and para-position of phenyl ring were tolerated, affording the products in moderate to high yields. The thiophene or cyclohexyl substrate also furnished the products in 23 and 39% yields, respectively. Based on the proposed mechanism, the reaction involves reduction of 146 by the excited photocatalyst affording the •CHF₂ radical 147. The subsequent addition of 147 to the C=N bond of the isonitrile group affords the radical 148 which next cyclizes to 149 via a 6-endo path. The alternative three-step cyclization path is also considered. The obtained radical is next oxidized to 150 and after H⁺ abstraction the final product is formed. Shen and coworkers have developed a metal-free, visible-light photoredox-catalyzed three-component reaction for the facile assembly of fluoroalkylated pyrimidine derivatives in a regiodefined [3 + 2 + 1] manner, starting from readily available building blocks of silyl enol ether, amidine, and fluoroalkyl halide (Scheme 38) [108].

A concise, two-step, one-flask procedure was designed for the synthesis of the test pyrimidine derivative (84% yield) by using benzamidine hydrochloride, triisopropylsilyl enol ether (1.8 equiv.), perfluorobutyliodide (3 equiv.), DABCO (3 equiv.), and Eosin Y (3%) as the photocatalyst. With the optimal reaction conditions in hand, the authors successfully extended the substrate scope of the reaction to benzamidines containing diverse substituents of varying electronic character and steric hindrance on the phenyl moieties, affording the corresponding products in high yields (70–98%). In the same manner, the reactions worked equally well with heteroaryl amidines and C-alkylated reactants. The substrate scope with respect to a series of structurally varied silyl enol ethers also led to satisfactory yields. In addition to perfluorobutyl iodide, the applicability of this transformation to a broad spectrum of fluoroalkyl halides (C₂F₅I, C₅F₁₁I, C₇H₁₅I, and C₈F₁₇I) was observed. According to the proposed mechanism, the reaction involves a single-electron transfer from the excited photocatalyst EY* to fluoroalkyl halide to produce the •C₄F₉ radical and a radical cation EY^•+. Next, tertiary carbocation 153 is generated via the addition of a perfluoroalkyl radical to the C=C bond of silyl enol ether 151, followed by further oxidation with the aid of the oxidative radical cation EY^•+. After rapid attack by an I⁻ ion, the α-perfluoroalkylated ketone 154 is formed. In a defluorination step, α,β-desaturation of 154 is enabled by eliminating a molecule of HF under basic conditions, affording 155. Finally, ring closure involving intermolecular [3 + 3] condensation of 155 with amidine 156 proceeds to afford the final product. It is worth noting that the reaction allowed efficient access to heterocyclic adducts with appreciable yields by utilizing in situ formed enolsilanes 151 from related ketones, followed by exposure to photocatalytic conditions in a single reaction vessel.

8. Conclusions

This review demonstrates that visible-light-driven photocatalysis contributed essentially to the development of reactions, allowing the easy formation of fluorinated aromatic compounds. Diverse methods to install a fluorine atom or the fluorine-containing moiety have been successfully employed, including generation of reactive perfluoroalkyl radicals by direct reduction of the C-I bond in perfluoroalkyl iodides, single-electron reduction of trifluoromethylsulfonyl chloride, hypervalent iodine, and sulfur compounds, or oxidation of sodium triflinate. The monofluorination of arene procedures are noteworthy, including addition of the fluorine anion to the aryl radicals formed in the photocatalytic cycle. Interestingly, we have seen progress in the development of new fluorine-containing precursors allowing the introduction of SCF₃, OCF₃, or SO₂F moiety to the aromatic system. The photocatalytic fluorination of arenes in a dual catalytic system (Ir/Cu or Ru/Cu) enabled the easy fluorination of a variety of arenes. In particular, the strategy developed by MacMillan’s group is noteworthy, allowing a general trifluoromethylation of aryl bromides through dual copper-photoredox catalysis by overcoming the copper oxidative addition problem with an aryl radical capture mechanism. The novel strategy exploiting a tandem relay by combining organo-photoredox-catalyzed radical fluoroalkylation and post-photocatalytic aromatization provides a general and highly efficient method for the one-pot synthesis of quinolines and pyrimidines from acyclic starting materials. In spite of its attractive features such as synthetic simplicity, a broad substrate scope, and excellent functional group compatibility under mild reaction conditions, further research work in this field is still needed. We predict that merging of different photocatalytic approaches to incorporate perfluoroalkyl groups will be developed, such as scale-up flow synthesis and enantioselective catalysis, which would result in novel types of fluorinated aromatic compounds which will serve in agrochemical, pharmaceutical, and material chemical industries.